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Review
. 2020 Sep 9:10:468.
doi: 10.3389/fcimb.2020.00468. eCollection 2020.

Increasing Evidence That Irritable Bowel Syndrome and Functional Gastrointestinal Disorders Have a Microbial Pathogenesis

Caterina Carco  1   2   3   4 , Wayne Young  2   3   4 , Richard B Gearry  4   5 , Nicholas J Talley  6 , Warren C McNabb  2   4 , Nicole C Roy  2   4   7   8
Affiliations
Review

Increasing Evidence That Irritable Bowel Syndrome and Functional Gastrointestinal Disorders Have a Microbial Pathogenesis

Caterina Carco et al. Front Cell Infect Microbiol. .

Abstract

The human gastrointestinal tract harbors most of the microbial cells inhabiting the body, collectively known as the microbiota. These microbes have several implications for the maintenance of structural integrity of the gastrointestinal mucosal barrier, immunomodulation, metabolism of nutrients, and protection against pathogens. Dysfunctions in these mechanisms are linked to a range of conditions in the gastrointestinal tract, including functional gastrointestinal disorders, ranging from irritable bowel syndrome, to functional constipation and functional diarrhea. Irritable bowel syndrome is characterized by chronic abdominal pain with changes in bowel habit in the absence of morphological changes. Despite the high prevalence of irritable bowel syndrome in the global population, the mechanisms responsible for this condition are poorly understood. Although alterations in the gastrointestinal microbiota, low-grade inflammation and immune activation have been implicated in the pathophysiology of functional gastrointestinal disorders, there is inconsistency between studies and a lack of consensus on what the exact role of the microbiota is, and how changes to it relate to these conditions. The complex interplay between host factors, such as microbial dysbiosis, immune activation, impaired epithelial barrier function and motility, and environmental factors, including diet, will be considered in this narrative review of the pathophysiology of functional gastrointestinal disorders.

Keywords: diet; functional gastrointestinal disorders; host-microbe interactions; human microbiota; immunity; irritable bowel syndrome; motility; visceral pain.

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Figures

Figure 1
Figure 1
Schematic representation of IBS pathophysiology. Psychological, physiological and neuro-gastroenterological factors are thought to be involved in the generation of IBS symptoms, including bloating, abdominal pain and altered motility. Created with BioRender.com.
Figure 2
Figure 2
In subjects with post-infectious IBS, the infection by certain pathogens, such as Clostridium difficile (Wadhwa et al., ; Bassotti et al., 2018), Salmonella (McKendrick and Read, 1994), Shigella (Gwee et al., ; Wang et al., 2004) or Escherichia coli (Marshall et al., 2006) compromises the integrity of the epithelial barrier, triggers inflammation and decreases microbial diversity and beneficial bacteria, detrimentally affecting GI microbiota composition (Jalanka-Tuovinen et al., 2014). The microbiota composition in post-infectious IBS subjects differs from both IBS subjects and healthy controls, featuring an increase in Bacteroidetes, which are usually decreased in general IBS, and a decrease in Firmicutes, including Clostridium clusters III, IV and XIVa (Sundin et al., 2014). Created with BioRender.com.
Figure 3
Figure 3
Comparison between mucosa-associated and luminal microbiota. Although luminal and colonic mucosal associated microbiota can potentially interplay with the immune system and therefore be involved in FGID symptomatology (Pittayanon et al., 2019), the fecal microbiota is not fully representative of the mucosal microbiota at the site of disease. Taxonomical and diversity differences between luminal and colonic mucosal microbiota highlight the importance of comparing the microbial composition in both niches, when analyzing the role of the GI microbiota in FGIDs. The colonic mucosa-associated microbiota seems to be predominantly characterized by Bacteroidetes (Rangel et al., ; Tap et al., 2017) and Lachnospiraceae (Hugerth et al., 2019), whereas the fecal microbiota by Firmicutes, Actinobacteria (Rangel et al., ; Tap et al., 2017), a higher relative abundance of Ruminococcaceae (Hugerth et al., 2019), and a higher bacterial diversity compared to the colonic mucosa-associated microbiota (Rangel et al., 2015). Microbial abnormalities in IBS subjects have been reported to be more pronounced in fecal samples than in colonic mucosal samples and the separation between mucosal and fecal microbiota composition was more distinct in IBS subjects than in healthy controls (Rangel et al., 2015). Whether IBS symptomatology is associated with taxonomical differences in the luminal and/or mucosal microbiota still remain to be determined. Created with BioRender.com.
Figure 4
Figure 4
Host-microbe interactions mediated by SCFAs. G-protein-coupled receptor expressed on intestinal epithelial and immune cells are activated by SCFAs. In particular, acetate and propionate are the most efficient agonists for GPR43 and GPR43, followed by butyrate and then other SCFAs (Kim et al., 2013). Propionate agonizes GPR43 on colonic regulatory T cells to inhibit HDAC function and enhance FOXP3 expression, thereby promoting regulatory T cell differentiation and IL-10 production. Although acetate is a potent GPR43 ligand, and mediates colonic regulatory T cells accumulation, it is not clear whether this is through this receptor (Kim et al., 2013). Butyrate has similar effects by either stimulating dendritic cells and macrophages to produce IL-10, or directly acting on naive T cells, inhibiting the activity of HDAC on the Foxp3 gene, inducing naive CD4+ T cells differentiation and regulatory T cell expansion (Kim et al., 2013). Butyrate can induce the production of TGF-β and cytoprotective IL-18 by the enterocytes through the activation of GPR109A. In addition, butyrate can inhibit NF-κB signaling, reducing the expression of pro-inflammatory IL-8 and TNF-α (Kim et al., 2013). On the other hand, SCFAs can mediate protective immunity, activating GPR41 and GPR43 on GI epithelial cells and resulting in the production of pro-inflammatory chemokines and cytokines (Kim et al., 2013). Therefore, SCFAs contribute to the maintenance of intestinal homeostasis through multiple mechanisms. Created with BioRender.com.
Figure 5
Figure 5
The consequences of diet on a dysbiotic microbiota may lead to altered levels of these metabolites, resulting in GI symptoms. In the colon, the fermentation of dietary fiber results in changes in the microbiota composition, supporting the growth of beneficial bacteria. Consequently, the microbiota generates gases, SCFAs and other metabolites. The microbial metabolism of lipids entering the colon is involved in several important pathways for the host. The families Erysipelotrichaceae and Coriobacteriaceae also play an important role in the conversion of cholesterol-derived metabolites, such as bile salts and steroids (Martínez I. et al., 2013). Altered bile acid metabolism has been associated with chronic inflammation in the colon (Devkota et al., 2012) and microbiota-derived bile acid metabolites have the potential to affect both host metabolism and immune responses (Alimov et al., 2019). The microbiota-mediated protein metabolism is largely affected by the proteolytic activity of amino acid-fermenting bacteria, mainly Clostridia and Peptostreptococcus, but also Bacteroides spp., Propionibacterium, Fusobacterium spp., Streptococcus, Lactobacillus, Veillonella spp., Selenomonas ruminantium and Megasphaera elsdeniiare (Yang and Yu, 2018). The microbial catabolism of amino acids occurs mostly through deamination and decarboxylation (Bertrand et al., 2014) and can generate immuno-modulatory molecules and neurotransmitters (like catecholamines) that have effects on both the immune and the nervous system. For example, the microbial glutamate decarboxylases convert glutamate into gamma-aminobutyric acid, which has immunomodulatory effects in the GI tract (Baj et al., 2019). Histamine, derived from the bacterial decarboxylation of L-histidine, can inhibit the release of pro-inflammatory cytokines via the histamine type 2 receptor on epithelial cells (Thomas et al., 2012). Hydrogen sulfide is thought to be responsible for an increased visceral hypersensitivity related to colonic distension, for altered colonic motility (Tsubota-Matsunami et al., 2012) and other deleterious effect on the colonic epithelium (Jorgensen and Mortensen, 2001). SRB: sulfate-reducing bacteria; BCFAs: branched-chain fatty acids. Created with BioRender.com.
Figure 6
Figure 6
Potential role of mast cells in IBS and chronic low-grade inflammation. Mast cells are thought to play a role in the onset of abdominal pain, as well as diarrhea or constipation. These symptoms are modulated by the mediators released by activated mast cells of the GI mucosa, which stimulate other immune cells, perpetuate chronic inflammation and alter secretion and peristalsis, resulting in abnormal GI permeability and motility. Mast cells, located close to nerve fibers, are thought to trigger pain signals. The mediator histamine sensitizes the nociceptor transient receptor potential channel V1 on peripheral nerve terminal of nociceptive submucosal neurons, resulting in visceral hypersensitivity (Cenac et al., 2010). Studies on rectal biopsies from IBS subjects demonstrated that the histamine H1 receptor-mediated stimulation of the nociceptor transient receptor potential channel V1 was potentiated in IBS subjects but not in healthy controls (Wouters et al., 2016). Proteases degranulated by mast cells may also destroy various epithelial gap junctional proteins (e.g., zonula occludens), leading to impairments in epithelial barrier function. Alterations in motility seem also to be linked to mast cells' degranulation. In particular, the stimulation of prostanoid receptors P2X on smooth muscle cells generates the excitatory potential responsible for contraction, impacting on smooth muscle contractility (Zhang L. et al., 2016). Created with BioRender.com.
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